Tumorigenesis is a complex process which has not been fully characterized to date. Mechanisms of tumorigenesis are the subject of intensive research since there is a continuing need for pharmaceuticals capable of interrupting a cascade of events leading to tumor formation. A number of causative events may trigger a tumorigenic cascade, including viral infection, spontaneous transformation, exposure to toxins among others.
Infection with Human Papllomaviruses (HPV) is believed to be one such causative event. Human Papllomaviruses are implicated in causation of nearly all cases of cervical cancer. Certain types of HPV are termed “high-risk”, in that infection with them is associated with development of high-grade cervical dysplasias which may progress to carcinomas.
HPVs, a subset of the papillomaviruses, are members of the Papillomaviridae family of viruses (31). The HPVs are small, double stranded, circular DNA viruses with an icosahedral, non-enveloped virion of about 55 nm in diameter and a genome of 8 kb. HPVs infect human squamous epithelium and induce papillomas (or warts). While there are many types of HPV able to infect various anatomical regions, it is the HPVs that infect the anogenital region that have been the best studied. Among this group, HPVs can be divided based upon the frequency with which they induce malignancy. The low risk HPVs can cause benign warts, but are rarely observed in malignant cancers. This group is represented by HPV types 6, 11, 42, 43, and 44. HPV types 16, 18, 31, 33, 39, 45, and 56 constitute the high risk HPVs, which are most often associated with malignant cervical cancers (2).
HPV is the prime etiological factor in the development of cervical cancer, being associated with over 90% of all cases (32). In addition to this epidemiological statistic, the IARC ultimately declared HPV 16 and 18 carcinogenic in humans (33) based upon a number of pieces of evidence including in vitro immortalization differences between high risk and low risk viruses (high risk HPVs can immortalize keratinocytes and low risk HPVs cannot (34) and the presence of active viral genomes and oncoproteins in cells of the tumor and associated metastases (35, 36, 37, 38).
Estimates vary, but in the US about ⅓ of college women show evidence of HPV infection. HPV infection typically manifests itself as cervical intraepithelial dysplasia (CIN) of three types, mild dysplasia or CIN1, moderate dysplasia or CIN2 and severe dysplasia or cervical carcinoma, referred to as CIN3. The mean age for CIN1 and CIN2 is 24-27 years, and for CIN3 is it 35-42 years. About 50% of CIN1 cases regress, whereas about 10% progress to CIN 3 and 2% progress to cervical cancer. While NIH-funded vaccine development shows promise, there are millions of patients who will develop CIN3 over the next 10 years, and who will require lifelong (>50 years) monitoring and treatment. The clinical problem may be even larger in developing countries. There are currently no effective therapies for HPV infections, aside from therapeutic cone biopsies, which often are followed by recurrent, progressive lesions.
Thus, there exists a need for compositions and methods for treating HPV infected cells and particularly for inhibiting growth of HPV-infected cells.